2-sulfanilamido-5-bromothiazoles



ture.

Patented Jan. 9, 1 951 Z-SULFANILAMIDO-S-BROMOTHIAZOLES Lucas P. Kyrides and Ferdinand B. Zienty, St.

Louis, 1710., assignors to Monsanto Chemical M0., a corporation of Dela- Company, StJLouis,

ware

No Drawing. Original application July 29,1944, Serial No. 547,276. Divided and this application September 17, 1945, Serial No. 616, 9 6

' .This invention relates'to certain brominated heterocyclic compounds and more particularly to 1 'a method of brominating certain heterocyclic compounds and to certain new and valuable mono-bromo amino-substituted heterocyclic 3 Claims. (Cl. 260-23935) compounds containing nitrogen and sulfur or" selenium' and their corresponding sulfanilyl derivatives.

This application is a division of my copending application, Serial Number 547,276, filed July'29,

1944, now Patent 2,457,078.

The substitution of bromine for hydrogen in many heterocyclic compounds is accomplished generally by adding bromine to a-cooled mixture 7 of the heterocyclic compound and an acid such as sulfuric acid, maintaining the reaction mixture 0001 during the reaction, and recovering the brominated product substantially at the temperature of the reaction or at a lower tempera- These low temperature procedures were lowing description and examples.

Other objects willbe apparent from the-'ffol- According to the present invention, generally stated, certain heterocyclic compounds may be "brominated by heating a mixture of the coinpound with an acidic substance or an acid,such as, hydrobromicacid, hydriodic acid, hydrochloric acid, or sulfuric-acid, and water to the temperature of refluenc of the mixture and thereupon slowly adding an equivalent amount ofbromine to the mixture. -The reaction isIei'r- -oth'ermic,- and the temperature of the, reaction mixture is maintained at reflux temperature during-the reaction substantially without theaid of external heat. When all of the bromine has been added, and the reaction has subsided, the reac- "tion mixture is cooled with agitation, for example..t0 room temperature. The product 'is isolated from the reaction mixture by any desired method; for example, when the product sepaemployed prior to the present invention" pre-" sumably because decomposition of the desired product was expected to take place at higher temperatures. Howeven'there are instances in which the bromination at the lower temperatures results inproducts'other than those which are desired from the reaction. For example, while 2-amino 4-methylthiazole may 'be brominated and the resulting 2-amino-4-methyl-5-bromothiazole recovered at the lower temperatures, we have found that the bromination of Z-aminothiazole according to this procedure results in a product which ha's'two 'ionizable bromine residues per molecule, as evidenced by titration with a standard silver nitrate solution. Moreover, the yields were poor, and the product failed to react satisfactorily with N-acetyl-sulfanilyl chloride, producing large amounts of tar.

The object of this invention is to provide a novel bromination procedure for substituting bromine for hydrogen in the ring structure of certain heterocyclic compounds.

A further object is to provide a novel process "for brominating Z-aminothiazole and its derivatives.

Another object is to provide certain novel ,brominated amino-substituted 'ti-membered hetl'roc'yclic compounds.

"Another objectis to provide. certain novel'sulfanilyl derivatives of'certain brominated aminosubstituted 5-mei'nbered heterocyclic compounds.

Another object is to provide a novel brominated Z-aminothiazole.

Another object is to provide a novel sulfanilyl bromo derivative of 2-aminothiazole.

rates out on cooling to room temperature, the product may be filtered off and airedried. If the product remains in solution after cooling to room temperature, the solutionmay be evaporated to induce a precipitation of the product. If the productisprecipitated while the solution is hot .or ;at theboiling point, it may be desirable to filter the solution while it is hot to effect a more efiicien-t removal of impurities dissolved in the .mother liquor.

V The bromination process of the present invention is applicable to the bromination of an olefiniccarbon atom of S-membered amino-substituted heterocyclic compounds which containin the ring structure at least one nitrogen atomat least one sulfur or selenium atom and 'a formation in the ring represented by and which are stable in the presence of acids or acidic substances. Some. of the heterocyclic compounds to which the process of the present invention applies are the'aminothiazoles, the amincselenazoles, the 4-alky1 and. 4-alkenylaminothiazoles and aminoselenazoles, the alkyl aminothiazoles and aminoselenazoles, 2-a'minodiazoles. The resulting mono-bromo compounds are useful as anti-bacterial and anti-'protozoal agents and as intermediates for the preparation of pharmaceuticals, dyestufts, textile treating agents and fungicides. The N-sulfanilyl derivatives of these compounds are of particular interest in combating micro-organisms. v

. When the process of the present invention is 5-bromothiazole.

as low as C'., or even lower; bromination operation, the reaction mixture is ing the addition of the bromine.

applied to the bromination of Z-aminothiazole, the product recovered from the reaction mixture is 2-amino-5-bromothiazole hydrobromide, having the formula:

The free base is obtained by neutralization of the hydrobromide with an alkali...

- The product resulting from the bromination of Z-aminothiazole by the method of the; present invention has been found to react in the free base fo rm with. N-acetyl-sulfanilyl. chloride to produce the novel compound, 2-N -acetyl-sulfanil'amido- This compound is then nydrolyzedv with alkali to yield the compound 2 sulianilamido--bromothiazole, having the formula:

example, 5- to 55 C., and the resulting'reaction =mixture then heated to the boiling point and boiled for ashort' time, for exampleseveral minute's. The bromination maybe conducted at temperatures just above the freezing point of the reaction mixture, which in some instances may be time.

'a'further alternative embodiment of the Following the process of the present invention,-the addition of V bromine to the reaction mixture may be effected {during the operation of heating the solution to the boiling point, proceeding cautiously, however,

the novel process and products of the present invention. These examples are to be construed merely as illnstrativegand not as limiting the scope of the invention, which is applicable to the bromination of heterocyclic compounds of the type hereinbefore described.

Example I A mixture of 150 g. (1.5 moles) of 2-aminothiazole, 300 cc. of water and 250 g. of 48% hydrobromic acid (1.5 moles) was heated to reflux tem-- ,perature, and 240 g. (1.5 .moles) (Z-731cc.) of bromine was added tothe mixture over a period of'about .35 minutes. The bromination reaction T .was'exotherinic, since the "batch remained at re flux temperature without external heating dur- When all the bromine had been added, the mixture was cooled -to,25 C. with stirring and thecrystals which separated out were filtered'and air d'ried. Yield,

Non-ioni-zable Ionizable bromine 30.2%; theory 30.8%.

180 g. of pink crystals; melting point 140-141" C. The product was 2-amino-5-bromothiazole hydrobromide. This salt Was recrystallized from water, using 160 cc. and 5.0 g. of decolorizing charcoal 101' every 109 g. of. 2-amino-5-bromothiazole hydrobromide. The filtered liquor Was treated with 0.1 g. of sodium hydrosulfite and cooled to 15 C. The crystals which separated were filtered off and dried. The melting point was 141-142 C. The 2-amino-5-bromothiazole hydrobromide was found to contain Z molecule of water of crystallization as shown by titration, using the Karl Fischer method. Assay, 100.6% of the hydrate by titration with silver nitrate. bromine 30.1%; theory 30.8%.

The 2- amino-5- bromothiazole hydrobromide is useful as an anti-bacterial agent, and as an intermediate in the preparation of dyestuffs, textile treating agents, fungicides, insecticide toxicants and pharmaceuticals. After two additional recrystallizations from water. the product melted at 144-145 C.

Example 11 .Aslurry of 10%) get wet recrystallized Z-amino- S-bromothiazole, prepared according to the method of Example I and. containing less than 5% moisture, and 409 cc. of water. was stirred and cooled below 5' C. A sol-utionof '32-.0 g..of sodium hydroxide in. 50 cc. of. water was added to -.this-solution by meansof a dropping funnel, the

temperature. of the'batch being maintained below 5 C. The mixture was just alkaline to phenol-phthalein at the end of the neutralization; 0.3 g. of sodium hydrosulfite was added, and the mixture was stirred for 1hr. at 5 C. The gray-brown crystals of 2-amino-5-bromothiazole werefiltered ofi and dried in the air. Melting point of the crudeproduct, 102-103 C., forming a black melt. Yield, 63.2 g. (98%). The free base 2-amino-5-bromothiazole was recrystallized .from water, using 309 cc. of water and 0.4 g. of .decolorizing charcoal for each 10 g. of the amine. Recovery, 81%.; melting point 05-106 C. The '2- amino-S-bromothiazole is useful as an anti-bacterial agent and as an intermediatein the .prep'a .rationof dyestuffs, pharmaceuticals, textile treating agents,,..fungioides and insecticides.

Example III 300 cc. of anhydrous pyridine wascooled to 5 C., and 25.6.,g. (0.142 mole) of 2-amino-5-br0mothiazolaprepared according to the method of Example II. was added. A solution of the amine in pyridine was formed when the mixture was agitated. 40 g. (20% excess) of N-acetyl-sulfanilyl chloride was addedto the solution over a. period of about 15 min., keeping the tempcrature of the batch below 5 C. The mixture was stirred for about 15 hrs. at a temperature below 5 C. Water was added, pyridine was distilled out under reduced pressureandthe precipitate was filtered off and Washed thoroughly with water. After drying at C. the product weighed 30.7 g. ('69% yield) The product was 2-N -acetyl-sulianilamid0-5-bromothia2ole. It is'useful as an anti-bac- .terial agent and in the preparation of fungicides and in the treatment oitextiles.

Example IV A solution of 33.8 g. (0.01- mole) of '2-N 'acetylsulfanilamido-5-bromothiazole, prepared accord- 2% sodium hydroxide was refluxed for 1% hrs.

of decolorizing charcoal were added, and the mixture was filtered hot. The filtrate was cooled to 30% C., and a solution of 16 cc. of concentrated hydrochloric acid in 100 cc. of water was added to the filtrate over a period of about 1 hr. until the mixture was acid to litmus. The crystalline product was filtered off, washed with water and dried. The product was 2-sulfanilamido-5-bromothiazole. Weight, 26.1 g. (87% yield). The 2 -sulfanilamido-5-bromothiazole was purified by recrystallization from 50% acetone; yellow crystals. The melting point was indistinct; 1 decomposition took place .above.'190 C. Assay 101%. by alkali titration in acetone,

using a phenolphthalein indicator. The product is useful as an anti-bacterial agent, anti-protozoal agent, fungicide and textile treating agent.

Example V A solution of g. of sulfuric acid in 100 cc. of

water was prepared and cooled to C. To this solution 25 g. of 2-aminothiazole was added.

When the solid material was dissolved, the temperature of the resulting solution was raised to 55 C. and held at that temperature by means of external cooling while 36 g. of bromine (11.5 cc.) was slowly added. After the reaction was complete, the solution was heated to boiling and boiled for approximately 2 min. to remove excess bromine. Thereafter the solution was cooled approximately to room temperature, 011125 to 6;; and allowed to stand at that temperature.

Crystals of 2-amino-5-bromothiazol'e hydrobroniide separated from the solution and were filtered 01f and dried. Yield 6.5 g.; melting point 139-14? C. The filtrate was cooled to a temperature slightly below 5 C; whereupon a second crop of crystals was obtained. These were filtered off and dried. Melting point 140-142" C.

The remainingliquid was evaporated to a small volume and cooled. A third crop of crystals was obtained. Melting point 139-l40 C. Total yield 13.9 g. or 23%. Non-ionizablebromine 30.2%; theory 30.8%. Ionizab1e'bromine 29%; theory 30.8%. from water, 141-142" C.; me1ting point after two additional recrystallizations from water, 144- 145 C.

Example VI ':.A=:solution of 25 g. of sulfuric acid in.-20 cc.

of water was cooled to 30 C. Tothis solution 50 g. of Z -aminothiaZole was added and dissolved therein. The temperature of the solution was brought to 30 C. and held at that point by means :1...

of 'external' cooling while 40 g. of bromine (12.9

='cc.) was slowlv added. The solution was stirred over-night. The following day 40; g. of bromine were added over a 2 -hr. period, the temperature .being maintained at 30 C. The solution was evaporated atroom temperatureto a; small volume. Crystals separated out and were filt red oif and dried. Yield 63 g. Ionizable bromine 58%: theory'for 2-amino-5-bromothiazole, hy-

d'robromide, 30.8%. This example illustrates the result of applying the customaryprocedure in endeavoring to brominate 2-aminothiazole. The melting point of the resulting prc j'gluct was found to be below 115 C. Attempts to form the N- acetyl sulfanilyl derivative of the product were unsuccessful. However, if the bromination reaction mixture is heated to the boiling point for several minutes before recoveryfiof the product, the desired 2-amino-5-bromothiazole compound is obtained.

Melting point after one crystallization' ExamplelVII A z-aminosele'nazole may be'brominated accord ing to the process described in Example I. The resulting product is 2-amino-5-bromoselenazole hydrobromide, having. the formula:

, B1'C ,o NHi.HBr

so I Example VIII The process describedin Example I may be repeated using Z-methylaminothiazole in place of 2-aminothiazole. The resulting product is 2- methylamino 5 bromothiazole hydrobromide, having the formula: s 1 Y HCN,

j I! g Br-C NH.CHs.HBr

Other allryl and alkenyl residues having from 1 -22 carbon atoms may be substituted for the methyl group on the amino residue, for example, the ethyl, isopropyl, butyl, amyl, octyl, decyl,

dodecyl, heptadecenyland eicosyl residues.

' Example IX .The process of Example I may be repeated .using Z-amino-1,3,4-thiadiazole. The resulting product is 2-amino-5-bromo-1,3,4-thiadiazole,

having the formula; 7

Example"?! '2-methylamino-1,3,4-thiadiazole may be brominated according to the method of Example I. The resulting product is 2-methylamino-5- bromo-1,3, l-thiadiazo1e hydrobromide, having the formula:

2-amino-4-methy1thiazo1e may be brominated according tothe method of Example I. The resulting product is 2-amino-4-methyl-5-bromothiazole hydrobromide', having the formula:

Other alkyl and alkenyl residues having from l-22 carbon atoms may be substituted forthe methylgroupon the ring structure, for example,

the ethyl, isopropyl, butyl, amyl, octyl, decyl,

Other alkyl and alkenyl residues having from 1-22 carbon atoms may be substituted for the ethyl group on the ring, for example, the methyl,

I isopropy'l, buty1,"am3rl;,:ontyl, decyl, dodecyl, heptadeoenyl and eicosyl residues...

Example," XIII The process -of Example I'may b'e repeated,

Other alkyl' and allienyl residueshavihglfrom 1-22 carbon atoms may be suti'stituted for the amyl residue on the rihg'structure and the methyl residue iomthe. amino group, for example, the ethyl, isopropyl, butyl, octyl, decyl, dodecyl heptadecenyl andv eicosyl residues.

Exampie' *The free base; derivatives' of the. bromo: com.-

pounds" describedin: Examples: may" be prepared by alkalinization of the hydrobromide salts according to the method of Example III The- N -acetyl sulf-anilamido derivatives' of the free base bromo' compounds-z cor responding tothe hydrobromid'e salt compounds of Examples VII-XIII may-lie prepared according to the method-oi Example III. The acetyl residue the resultingpcom-pounds may be hydrolyzed oil by themethod of Example IV. The resulting 2-sulfanilamido bromo compounds" are:

Example, VIL.-2.. sulfanilamido. -U5 bromoselenazole, having the iormulaz M Sc Example VIm'r-N! --methy1- -=2 sulfanilamido 5 bromothiazole, having the formula:

Example; IXi-AZ: sulfanilamidoia 5? bromo- 1,3,4 thiadiazole, having the: formula:

H N-'N C-Br ' Examples X. NI methyL-2;.- sulfanilamicio- 5;- bromo,- 133A thiadiazole, having; the for.

Example; XI.e-2 sulfaniiamido: ew metham- 51.-- bromothiazole, having, the formula:.

Example) XIHl-N' methyl: 2' snlfanilav midb=-42- amylf-fii- :bromothiazole; having the- The sulfanila-midwbromo derivativesof: thevcompounds ofiExamples. VILIX, XI and X11 maybe employed as: anti-bacterial agents;- asinsecticide;

toxioants; andas surface-active; agents;

We: claim:

amido-fi-bromothiazole; havin theformula;

' Hv N--GH ZNQSOPILi-Pi karr wherein. ZN; represents a; radical selected-1 from the: group. consisting ofsjtheamino: group) and.

theitacetyl amino group: I

2::As'= a" new compounch, 2-N -acetyl-suliamilamido:-5.i-bromothiazole;, having the: formula;

formula LUCAS FERDINAND B.-

REFERENCES? CITED Thek'following references are of record; m the fiie 'ofthi's patent? UNITED STATES PATENTS Number" Name Date $332,906; Eoldi et a1: ,Oct.--26,- 1943 Roblin et a1; septum, IQAQ 1 OTHER REFERENCES Berichte voll 72-13, pp. 14701-1476 (193.9);.

[;Citing Jensenuet a1. inDansk. Tids. Earm..15,

Wiselogel: Survey; ofc Antimalarial; mugs, rant-49.45: (1.; Wsndwams; AnIL Arl5o1:, mm.

As a" new: compound; z-sulfamlamidoefibromothiazole, havin the ChemMAbsN vol 38. (April,v 19.44) page. 1483 Certificate of Correction Patent No. 2,537,592 January 9, 1951 LUCAS P. KYRIDES ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 5, line 3, for 30% read 30; column 8, line 38, for that portion of the formula reading H "03.30.15" r onto o.1 'r

and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 6th day of March, D. 1951.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. AS A NEW CHEMICAL COMPOUND, A 2-SULFANAMIDO-5-BROMOTHIAZOLE, HAVING THE FORMULA: 